The hematopoietic system is exquisitely sensitive to radiation damage. Otherwise survivable doses of acute radiation will cause irreversible bone marrow failure and death in humans. To date, the only curative approach is cell replacement therapy using transplanted bone marrow or peripheral blood hematopoietic progenitor cells. However it is not feasible to use this therapy for treating acute radiation induced injury. Alternative approaches that are focused on identifying methods to mitigate radiation induced cell death and promote host hematopoietic regeneration are urgently needed. Initial studies from our laboratory revealed that factors produced by blood vessel derived endothelial cells can regenerate hematopoiesis and prevent death after exposure to gamma radiation. This experimental system provides a novel approach to identify the cellular and molecular mechanisms responsible for the radioprotection of bone marrow. The goal ofthis proposal is to exploit this model to identify the factors and signals elaborated by endothelial cells that mediate the regeneration ofthe hematopoietic system. To accomplish this we propose to develop strategies to augment hematopoietic recovery following bone marrow lethal doses of radiation. The first aim will identify the diverse cellular mechanisms responsible for endothelial cell mediated radioprotection ofthe hematopoietic system. In the second aim we will determine the molecular mechanisms that govern hematopoietic regeneration and identify candidate radioprotective factors. RNA sequencing will be used to obtain non-biased patterns of gene expression associated with key transcriptional responses that mediate hematopoietic cell radioprotection. The ultimate goal ofthis research is to identify therapeutic factors that can enhance the regeneration of the hematopoietic system following radiation injury.